Aim: Anti-angiogenic therapy is increasingly used in cancer patients but therapeutic response is heterogeneous and predictive biomarkers for patients stratification are currently lacking. In a previous study, it has been observed that levels of "glucose addiction" modulate the pathologic response of tumor xenografts to VEGF neutralization. Here we investigated whether the glycolytic phenotype affects therapeutic responses to anti-angiogenic therapy by evaluating cell proliferation and regional hypoxia changes at early and late time-points by in vivo PET imaging with [18F]FLT and [18F]FAZA, respectively. Materials and methods: SCID female mice were injected in the upper right back part with 4 x 105 poorly glycolytic IGROV-1 cells (n=20) or 3 x 105 highly glycolytic OC316 cells (n=20) mixed with liquid Matrigel. Following generation of tumor xenografts, mice were randomized into two groups: control (n=10) and treated (n=10). Bevacizumab (Avastin; i. p. 5 mg/kg) administration started when tumors reached 90-100 mm3 volume and lasted for 4 weeks (9 doses). Animals underwent PET with [18F]FLT and [18F]FAZA at the baseline and 7 and 28 days from the beginning of therapy. Quantification analysis was performed with pmod 2.7 software and max radiotracers uptake values (SUVmax), tumor to background ratio and metabolic volumes were obtained. Finally, histological and immunohistochemical analysis were performed. Results:We found that at 7 days the volume of highly glycolytic treated tumors was smaller than controls but there were no differences in radiotracers uptake. At the end of therapy, treated tumor volume measured at calliper was significantly increased from the baseline and tumors contained large necrotic areas. In contrast, in poorly glycolytic xenografts we observed an early but transient reduction in [18F]FLT uptake (7 days; p<0.05) and a long-term cytostatic effect as revealed by the lack of tumour volume increase up to 28 days. However, despite their small size, tumors treated with bevacizumab were composed by highly proliferative and hypoxic cells as shown by [18F]FLT and [18F]FAZA images. Conclusions: Bevacizumab arrests growth of poorly glycolytic tumours although it selects a more aggressive phenotype, as indicated by PET FLT and FAZA PET studies. Moreover, lack of reduction in FLT uptake might be predictive of early onset anti-VEGF resistance associated with the highly glycolytic phenotype, despite the transient reduction in tumour volume present at early times. Acknowledgements: This research has been supported by AIRC Project Molecular and Cellular Imaging of Cancer and by PIO Project PET Molecular Imaging.
Evaluation of response to therapy in ovarian cancer models with different glycolytic phenotype using in-vivo imaging PET
Silvia Valtorta;Rosa Maria Moresco;Giuseppe Di Grigoli;
2012
Abstract
Aim: Anti-angiogenic therapy is increasingly used in cancer patients but therapeutic response is heterogeneous and predictive biomarkers for patients stratification are currently lacking. In a previous study, it has been observed that levels of "glucose addiction" modulate the pathologic response of tumor xenografts to VEGF neutralization. Here we investigated whether the glycolytic phenotype affects therapeutic responses to anti-angiogenic therapy by evaluating cell proliferation and regional hypoxia changes at early and late time-points by in vivo PET imaging with [18F]FLT and [18F]FAZA, respectively. Materials and methods: SCID female mice were injected in the upper right back part with 4 x 105 poorly glycolytic IGROV-1 cells (n=20) or 3 x 105 highly glycolytic OC316 cells (n=20) mixed with liquid Matrigel. Following generation of tumor xenografts, mice were randomized into two groups: control (n=10) and treated (n=10). Bevacizumab (Avastin; i. p. 5 mg/kg) administration started when tumors reached 90-100 mm3 volume and lasted for 4 weeks (9 doses). Animals underwent PET with [18F]FLT and [18F]FAZA at the baseline and 7 and 28 days from the beginning of therapy. Quantification analysis was performed with pmod 2.7 software and max radiotracers uptake values (SUVmax), tumor to background ratio and metabolic volumes were obtained. Finally, histological and immunohistochemical analysis were performed. Results:We found that at 7 days the volume of highly glycolytic treated tumors was smaller than controls but there were no differences in radiotracers uptake. At the end of therapy, treated tumor volume measured at calliper was significantly increased from the baseline and tumors contained large necrotic areas. In contrast, in poorly glycolytic xenografts we observed an early but transient reduction in [18F]FLT uptake (7 days; p<0.05) and a long-term cytostatic effect as revealed by the lack of tumour volume increase up to 28 days. However, despite their small size, tumors treated with bevacizumab were composed by highly proliferative and hypoxic cells as shown by [18F]FLT and [18F]FAZA images. Conclusions: Bevacizumab arrests growth of poorly glycolytic tumours although it selects a more aggressive phenotype, as indicated by PET FLT and FAZA PET studies. Moreover, lack of reduction in FLT uptake might be predictive of early onset anti-VEGF resistance associated with the highly glycolytic phenotype, despite the transient reduction in tumour volume present at early times. Acknowledgements: This research has been supported by AIRC Project Molecular and Cellular Imaging of Cancer and by PIO Project PET Molecular Imaging.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
